The present invention is related to antibodies which specifically bind to the human gp130 receptor, hybridomas for producing such antibodies, and therapeutic uses of such antibodies to inactivate gp130 thereby treating diseases reliant on the gp130 receptor.
Interleukin 6 ( IL-6) is a multi-functional cytokine that exhibits a plethora of biological activities (Kishimoto, T., Blood, 1989, 74:1-10; van Snick, J., Annu. Rev. Inununol., 1990, 8:253-278; Akira et al., 1993, Adv. Immunol., 1993, 54:1-78). Among these are the induction of the hepatic acute phase response (Castell et al., FEBS Lett., 1989, 242:237-239), B cell antibody production (Muraguchi et al., J. Exp. Med., 1988, 167:322-344), maturation of megakaryocytes (Ishibashi et al., Proc. Natl. Acad. Sci. USA, 1989, 86: 5953-5957) and augmentation of platelet production (Ishibashi et al., Blood, 1989, 74:1241-1244). A number of other cytokines including leukemia inhibitory factor [LIF (Metcalf, D., Int. J. Cell Cloning, 1991, 9:95-108)], oncostatin M (Rose et al., Proc. Natl. Acad. Sci . USA, 1991, 88:8641-8645) , ciliary neurotrophic factor [CNTF (Schooltink et al., FEBS Lett., 1992, 314:280-284)] and interleukin 11 [IL-11 (Yonemura et al., Br. J. Haematol., 1993, 84:16-23)] also mediate similar biological effects. This apparent functional redundancy can be explained since their cellular signals are all transduced via common receptor .beta. chain subunit known as gp130 [CD130; (Kishimoto et al., Cell, 1994, 76:253-262; Taga et al., Cell, 1989, 58:573-581)]. Specificity is provided by the binding of the cytokine to its non-signal transducing .alpha. chain. Although this specific interaction is of relative low affinity, the cytokine-.alpha. chain binding facilitates interaction with gp130 to form a high affinity complex, resulting in dimerization and signal transduction.
Of this family of cytokines, IL-6 is the best characterized and has been studied in a variety of human diseases. Increased IL-6 production has been observed in inflammatory disorders, autoimmune diseases and cancer, and may be involved in their symptomatology and/or pathogenesis. Consequently, blocking the biological effects of IL-6 may have therapeutic utility in treatment of a number of disorders and diseases.
A number of different approaches to inhibiting IL-6 activity have been investigated. These include: (1) direct blockade of cytokine synthesis; (2) direct inhibition via anti-IL-6 antibodies; (3) inhibition of IL-6-mediated signal transduction via competition with various inactive IL-6 mutants; (4) inhibition of binding of IL-6 to the .alpha. chain of its receptor via anti-IL-6 receptor .alpha. antibodies; (5) inhibiting signal transduction with soluble forms of gp130; and (6) inhibition of signal transduction via anti-gp130 antibodies (Taga et al., Proc. Natl. Acad. Sci. USA, 1992, 89:10998-11001; Saito et al., J. Immunol. Meth., 1993, 163:217-223). The latter approach is not specific for IL-6 and is potentially suitable for inhibiting the biological activity of other members of the gp130 signalling family of cytokines.
Anti-IL-6 and anti-IL-6R antibodies have both been reported to be effective inhibitors of IL-6 both in vitro and in vivo. Anti-IL-6 antibody administration blocks myeloma cell proliferation in vivo, attenuating the activation of coagulation in experimental endotoxemia and ameliorating symptomatic rheumatoid arthritis in man. Anti-IL-6R antibodies have also been shown to inhibit the biological effects of IL-6 in animal models including abrogation of the IL-6-induced augmentation of the platelet count. Another potential approach would be to specifically inhibit the IL-6/.alpha. chain interaction as recently shown with the soluble IL-1 receptor. However, soluble forms of the IL-6 receptor .alpha. chain have been shown to be agonists in this system since they are capable of binding to IL-6 and associating with cellular gp130 (Mackiewicz et al., J. Immunol., 1992, 149:2021-2027). A novel approach has been the development of IL-6 mutants which inhibit the interaction of the IL-6/.alpha. chain complex with gp130 in vitro. Suramin has also been shown to inhibit IL-6 bioactivity in vitro and in vivo probably via non-specific receptor blockade or inhibition of signal transduction.
Although the potential role of the other cytokines of this family in the aforementioned disorders remains to be elucidated, blockade of the common gp130 subunit offers the possible advantage that one or more members of the IL-6 family of cytokines may be inhibited by a single specific antagonist. The efficacy of such an approach has been demonstrated in vitro with monoclonal antibodies (Mabs) raised against the extracellular domain of gp130 (Taga et al., Proc. Natl. Acad. Sci. USA, 1992, 89:10998-11001) as noted above.
Some cytokines such as IL-6 are crucial for the growth and development of certain malignant cells. Multiple myeloma for example, is a not uncommon malignancy in man in which inhibition of IL-6 by means of anti-IL-6 antibodies has been shown to ameliorate the disease process. IL-6 may be involved in the growth of lymphomas in patients with AIDS. The potential advantage for anti-gp130 therapy rather than specific anti-IL-6 therapy is that targeting this receptor molecule may inhibit not only IL-6 effects but also cell growth that may in part be mediated by other cytokines that share the gp130 pathway. For example, the cytokine oncostatin M which operates via gp130, has been implicated in the pathogenesis of Kaposi's sarcoma, a malignancy found in AIDS patients.
Since gp130 is a portion of the receptor for a number of cytokines that promote the acute phase response (including interleukin-11, leukemia inhibitory factor and oncostatin M), inhibition of that response with an antibody may well be employed as an anti-inflammatory agent, since the acute phase response is part of the inflammatory process.
Consequently, any disorder in which inflammation has a prominent component may be amenable to therapy. Common inflammatory disorders for which such therapies might be beneficial include rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease such as ulcerative coliris. Moreover, atherosclerosis and thrombotic disease may in part be related to inflammation. A therapy effective in targeting and inactivating the gp130 receptor would obviously be desired in the treatment of inflammatory disorders and other disorders or disease states which operate via the gp130 receptor.